This proposal will investigate the neural mechanisms associated with the well-documented effects of CB1 receptor blockade1 on extinction processes in a key associative learning circuit. The orbitofrontal cortex (OFC) is critically involved in the computations that compare expected versus actual reward outcomes2. Our prior studies showed that coincident changes in firing and subsecond dopamine release in the nucleus accumbens (NAc), a limbic-motor interface, are linked to cues that signal reward availability during brain stimulation reward (BSR) of the ventral tegmental area (VTA). Cue-evoked changes in DA release thought to encode a reward prediction error3, disipate under extinction conditions and are rapidly re-instituted folowing experimenter- delivered cues previously asociated with BSR4. This is mimicked by administration of a CB1 receptor antagonist. Here, we will investigate how endocannabinoid signaling in OFC modulates behavioral responding and real-time dopamine signaling during Pavlovian over-expectation. Preliminary data shows that OFC neurons exhibit short lasting bursts of activity during over-expectation2. This activity pattern is similar to that required to produce endocannabinoid-mediated plasticity in other cortical areas5-11. Given the ability of cannabinoids to impair reversal learning with specific OFC correlates12, we will investigate the role of endocannabinoid signaling in the OFC in extinction induced by over-expectation and accompanying changes in subsecond dopamine release in the NAc. These studies wil address how interactions between endocannabinoid signaling in OFC and phasic dopaminergic error signaling modulate learning. Interfering with or facilitating endocannabinoid tone in the OFC, upstream from dopamine cell bodies, may profoundly impact the way neural circuits respond to outcome-predicting environmental stimuli for learning. This hypothesis has never been directly tested because to do so requires selective modulation of endocannabinoids release at anatomically precise brain loci related to cognitive processes. Here, we wil isolate the afferent pathway recruited by endocannabinoids to produce patterned OFC activity during over-expectation. Specific genetic control of CB1 receptors on inhibitory afferents to OFC pyramidal neurons and optogenetic interrogation of this circuit will allow explicit tests of cortical endocannabinoid function and its impact on dopamine encoding of prediction errors during extinction training. By investigating interactions between dopaminergic and endocannabinoid signaling during learning in over-expectation, the present proposal will generate new insights relevant to extinction-based therapeutic strategies. PUBLIC HEALTH RELEVANCE: A major problem in the treatment of drug abuse is the renewal of drug craving and seeking upon environmental triggers, commonly known as relapse, after protracted abstinence periods. Clinical experience indicates that there are few effective approaches for use in crisis intervention, detoxification, stabilization and harm reduction in addicted patients. By employing new pharmacological tools with promising therapeutic value in a broad spectrum of addictive substances, a better understanding of the neurobiological mechanisms triggering relapse in the treatment of drug addiction and dependence will be gained.